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UW compound counters Avian flu

Madison, Wis. - Federal health officials may not be saying it, but they are frightened to death of the following scenario: an outbreak of the deadly avian flu virus begins quietly in scattered areas of the country, and spreads before they can get a handle on it - with substantial harm done to public health and the economy.

It's not an irrational fear, and one that is exacerbated by the lack of an electronic information exchange infrastructure. A promising new compound discovered at the University of Wisconsin-Madison might help them beat the clock, but it faces a long gauntlet of tests before it is used in humans.

The new antiviral compound, which was described online in a Journal of Virology report, protects against a broad array of influenza viruses, including avian influenza, at a time when existing antiviral drugs are losing their potency and amid heightened fears of an avian flu pandemic.

But time might not be on the side of researchers.

There currently are no effective vaccines for avian flu, although several experimental vaccines are being tested. While vaccines are the most important line of defense against an influenza epidemic or pandemic, they can take as long as a year to formulate and be manufactured in the required quantities. Antivirals can be used to buy time until large quantities of vaccines are produced, but existing antivirals are becoming less effective, and it will take time to develop replacements like the one represented in this new compound.
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"It's quite a ways down the road, unfortunately," said Stacey Schultz-Cherry, a UW-Madison professor of medical microbiology and immunology, and the senior author of the report. "It may be two to three years before we conduct clinical trials in humans."

The research team, which also includes report co-author Curtis Brandt, a UW-Madison professor of medical microbiology and immunology, would like to quickly move the research into the preclinical phase. The road ahead includes deciphering the peptide's precise mechanism for frustrating the flu, and work to determine optimal dosage, efficacy, and safety before the drug can be tested in humans.

Brandt's projected timetable is even longer. "If we had the funding now to start pre-clinical trials, we would be 4 to 5 years away from starting Phase I clinical trials," he said. "Phases one, two, and three of the clinical trials could take another three to five years."

Schultz-Cherry speculated that the development of this and other antiviral drugs could be fast-tracked, but that might only occur in the event of a flu pandemic. "I imagine there would be expedited drugs in the case of a public health crisis," she said.

One long-term scenario is that the new compound, like drugs used to treat the HIV infection, could be used as part of an anti-influenza cocktail of drugs.

Bars to entry

According to the Journal of Virology report, the UW-Madison researchers have found a flu-fighting peptide, a small protein molecule which is a fragment of a larger human protein. The peptide blocks the influenza virus from attaching to and entering the cells of its host, which prevents it from replicating and infecting more cells. It appears to work by thwarting the virus' ability to latch onto a key cell surface molecule that a virus uses to get inside.

The compound, known as "entry blocker," was tested on cells in culture and in mice, and pretreatment with the peptide provided 100 percent protection against numerous subtypes of flu, including the highly pathogenic H5N1 (avian) viruses. It also was highly effective in treating animals in the early stages of infection, the report said.

In contrast, infected animals that were left untreated usually died within a week, and infected animals treated at the onset with small doses of the drug survived.

At the moment, there are a few flu-fighting antiviral medications on the market, and they have worked either by preventing virus replication within the cell, or preventing the release of viruses from the cell. They are, however, beginning to lose their effectiveness, which has health professionals worried that the flu virus, including deadly strains like H5N1, will evolve to the point where existing drugs have no positive affect.

The new drug goes to work on a different part of the virus' life cycle, preventing it from even entering the cell, which essentially blocks the earliest step in infection.

The UW-Madison researchers aren't sure what happens to a virus when it cannot enter a cell, but they believe it induces some type of immune response. Brandt said the body's defenses include various enzymes that could chop up an inactivated virus, plus flushing mechanisms like tears and saliva.

One caveat is that the avian flu viruses do not appear to be good stimulators of the immune system, he added.

Campus collaborators

The team of scientists that discovered this compound had observed its flu-fighting capabilities after finding that similar peptides could prevent infection by the herpes simplex virus. It is not the same team led by UW-Madison professor of virology Yoshihiro Kawaoka, who will direct the UW's Institute for Influenza Viral Research, but it is one of several research teams that collaborate with it.

Its work is supported by grants from the UW-Madison School of Medicine and Public Health's Education and Research Committee, the National Institutes of Health, and the Defense Advanced Research Projects Agency.

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